The field of the invention is ultrasound methods and systems. More specifically, the field of the invention is noninvasive ultrasonic techniques for changing glomerular permeability in order to modify kidney ultrafiltration. In general, the present invention also relates to a therapeutic use of ultrasound that can be monitored using existing imaging techniques
There are a number of modes in which ultrasound can be used to produce images of objects. The ultrasound transmitter may be placed on one side of the object and the sound transmitted through the object to the ultrasound receiver placed on the other side (“transmission mode”). With transmission mode methods, an image may be produced in which the brightness of each pixel is a function of the amplitude of the ultrasound that reaches the receiver (“attenuation” mode), or the brightness of each pixel is a function of the time required for the sound to reach the receiver (“time-of-flight” or “speed of sound” mode). In the alternative, the receiver may be positioned on the same side of the object as the transmitter and an image may be produced in which the brightness of each pixel is a function of the amplitude or time-of-flight of the ultrasound reflected from the object back to the receiver (“refraction,” “backscatter,” or “echo” mode).
There are a number of well known backscatter methods for acquiring ultrasound data. In the so-called “A-scan” method, an ultrasound pulse is directed into the object by the transducer and the amplitude of the reflected sound is recorded over a period of time. The amplitude of the echo signal is proportional to the scattering strength of the refractors in the object and the time delay is proportional to the range of the refractors from the transducer. In the so-called “B-scan” method, the transducer transmits a series of ultrasonic pulses as it is scanned across the object along a single axis of motion. The resulting echo signals are recorded as with the A-scan method and their amplitude is used to modulate the brightness of pixels on a display. The location of the transducer and the time delay of the received echo signals locates the pixels to be illuminated. With the B-scan method, enough data are acquired from which a two-dimensional image of the refractors can be reconstructed. Rather than physically moving the transducer over the subject to perform a scan it is more common to employ an array of transducer elements and electronically move an ultrasonic beam over a region in the subject.
Ultrasonic transducers for medical applications are constructed from one or more piezoelectric elements sandwiched between a pair of electrodes. Such piezoelectric elements are typically constructed of lead zirconate titanate (“PZT”), polyvinylidene diflouride (“PVDF”), or PZT ceramic/polymer composite. The electrodes are connected to a voltage source, and when a voltage is applied, the piezoelectric elements change in size at a frequency corresponding to that of the applied voltage. When a voltage pulse is applied, the piezoelectric element emits an ultrasonic wave into the media to which it is coupled at the frequencies contained in the excitation pulse. Conversely, when an ultrasonic wave strikes the piezoelectric element, the element produces a corresponding voltage across its electrodes. Typically, the front of the element is covered with an acoustic matching layer that improves the coupling with the media in which the ultrasonic waves propagate. In addition, a backing material is disposed to the rear of the piezoelectric element to absorb ultrasonic waves that emerge from the back side of the element so that they do not interfere.
When used for ultrasound imaging, the transducer typically has a number of piezoelectric elements arranged in an array and driven with separate voltages (“apodizing”). By controlling the time delay (or phase) and amplitude of the applied voltages, the ultrasonic waves produced by the piezoelectric elements (“transmission mode”) combine to produce a net ultrasonic wave focused at a selected point. By controlling the time delay and amplitude of the applied voltages, this focal point can be moved in a plane to scan the subject.
The same principles apply when the transducer is employed to receive the reflected sound (“receiver mode”). That is, the voltages produced at the transducer elements in the array are summed together such that the net signal is indicative of the sound reflected from a single focal point in the subject. As with the transmission mode, this focused reception of the ultrasonic energy is achieved by imparting separate time delay (and/or phase shifts) and gains to the echo signal received by each transducer array element.
As indicated above, there are a number of electronic methods for performing a scan using a transducer having an array of separately operable elements. These methods include linear array systems and phased array systems.
A linear array system includes a transducer having a large number of elements disposed in a line. A small group of elements are energized to produce an ultrasonic beam that travels away from the transducer, perpendicular to its surface. The group of energized elements is translated along the length of the transducer during the scan to produce a corresponding series of beams that produce echo signals from a two-dimensional region in the subject. To focus each beam that is produced, the pulsing of the inner elements in each energized group is delayed with respect to the pulsing of the outer elements. The time delays determine the depth of focus which can be changed during scanning. The same delay factors are applied when receiving the echo signals to provide dynamic focusing during the receive mode.
The second common form of ultrasonic imaging is referred to as phased array sector scanning (“PASS”). Such a scan is comprised of a series of measurements in which all of the elements of a transducer array are used to transmit a steered ultrasonic beam. The system then switches to receive mode after a short time interval, and the reflected ultrasonic wave is received by all of the transducer elements. Typically, the transmission and reception are steered in the same direction, θ, during each measurement to acquire data from a series of points along a scan line. The receiver is dynamically focused at a succession of ranges, R, along the scan line as the reflected ultrasonic waves are received. A series of measurements are made at successive steering angles, θ, to scan a pie-shaped sector of the subject. The time required to conduct the entire scan is a function of the time required to make each measurement and the number of measurements required to cover the entire region of interest at the desired resolution and signal-to-noise ratio. For example, a total of 128 scan lines may be acquired over a sector spanning 90 degrees, with each scan line being steered in increments of 0.70 degrees.
The same scanning methods may be used to acquire a three-dimensional image of the subject. The transducer in such case is a two-dimensional array of elements which steer a beam throughout a volume of interest or linearly scan a plurality of adjacent two-dimensional slices.
Various ultrasound generated acoustic-mechanical effects can induce transient changes in vascular permeability and function. For example, low intensity focused ultrasound (“FUS”), whether alone or combined with the administration of a gas microbubble-based ultrasound contrast agent, has been shown to enhance the permeability of biological membranes. This phenomenon has been utilized in methods that seek to enhance the delivery of drugs or genes. Furthermore, other previous methods have shown that ultrasound bursts combined with a microbubble contrast agent can result in temporary disruption, or breaking down, of the blood-brain barrier. While the exact mechanism for the blood-brain barrier disruption is unknown, it appears that it may result from enhancement of the permeability of the endothelial cells or a widening of the junctions between the endothelial cells. In addition physiological changes induced or triggered by the ultrasound bursts employed in FUS may play a pivotal role. For example, electron microscopy studies have shown active vesicular transport as well as passive diffusion through widened tight junctions. During the sonications, temporary vasospasm associated with the ultrasound bursts has also been observed with in vivo microscopy.
The glomerulus is another vascular structure that functions as a barrier, and in its case, as one between the blood and the urine. Glomerular ultrafiltration is a hemodynamically regulated event that is modulated though the glomerular barrier. This barrier has physical properties that can be dynamically changed. These include the thickness of the glomerular basement membrane (“GBM”) and the slit diaphragm's spread of the epithelial layer. Such physical properties may be dynamically changed in order to increase, or decrease, the glomerular ultrafiltration coefficient, as needed to reach the filtration pressure equilibrium.
More specifically, the glomerulus is an ultrafiltration structure capable of filtering a large volume of plasma while retaining macromolecules in the circulation. The GBM and the cellular layers are responsible for maintaining this function. Recent studies on healthy animals, such as those described by W. M. Deen, et al., in “Structural Determinants of Glomerular Permeability,” Am J Physiol Renal Physiol, 2001; 281(4): F579-F596, have suggested that the glomerular ultrafiltration coefficient can dynamically change as a function of time to ensure the filtration pressure equilibrium and the stability of the glomerular ultrafiltration. Previous studies that examined the permselectivity of the glomerular membrane and the sieving of different size Dextrans, such as those described by R. L. Chang, et al., in “Permselectivity of the Glomerular Capillary Wall: Studies of Experimental Glomerulonephritis in the Rat Using Neutral Dextran,” J Clin Invest, 1976; 57(5):1272-1286, have found that filtration of 70,000 Dalton (“Da”) Dextran to the urinary space is extremely limited under normal circumstances.
The glomerular barrier plays a fundamental role in filtration impairment. For example, a decrease in the glomerular ultrafiltration is thought to originate in a decreased hydraulic permeability of the capillary wall (i.e., a substantial decrease in the glomerular ultrafiltration coefficient), a decreased surface area within the glomerulus, a decreased number of functioning glomeruli, or some combination of these factors, as described by A. B., Fogo in “Mechanisms of Progression of Chronic Kidney Disease,” Pediatr Nephrol, 2007; 22(12):2011-2022.
Patients with severe heart failure who are resistant to conventional kidney therapies have very high one-year mortality. Noninvasively increasing the GFR in these patients would cause excess water and salt to be gradually removed without compromising blood pressure and could help reverse sympathetic and rennin-angiotensin overactivity. The ability to alter GFR in a patient would also provide a temporary time-window to increase the filtration of even large molecules, such as toxins like Shiga toxin produced during E. coli 0157:H7 infection, which are normally not cleared by the kidney. Such a method could also enhance the efficiency of the detoxification of smaller molecules, such as Lithium, through a temporary GFR increase.
It would therefore be desirable to provide a non-invasive method for altering glomerular ultrafiltration by either directly modifying the membranes involved in ultrafiltration or otherwise triggering a vasoactive response using a mechanical stimulus that is highly targeted at the glomeruli. Such a stimulus would be a powerful tool that could open doors for novel renal therapies and provide a new method to study kidney function and disease.